A Phase I/II Trial of Hydroxychloroquine Added to Bortezomib for Relapsed/Refractory Myeloma
Overview
- Phase
- Phase 1
- Intervention
- bortezomib
- Conditions
- Multiple Myeloma and Plasma Cell Neoplasm
- Sponsor
- Abramson Cancer Center at Penn Medicine
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Overall response rate
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with bortezomib may kill more cancer cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of hydroxychloroquine when given together with bortezomib and to see how well it works in treating patients with relapsed or refractory multiple myeloma.
Detailed Description
OBJECTIVES: Primary * To establish the dose-limiting toxicities and maximum tolerated dose of hydroxychloroquine when added to a standard-dose regimen of bortezomib for treatment of patients with relapsed or refractory multiple myeloma. Secondary * To obtain a preliminary estimate of the toxicity rate and response rate of this combination at the maximum tolerated dose. * To confirm preclinical evidence showing synergistic effects of hydroxychloroquine and bortezomib by correlating response rate with blood levels of hydroxychloroquine and degree of autophagy inhibition in repeated bone marrow samples. OUTLINE: This is a phase I dose-escalation study of hydroxychloroquine followed by a phase II study. * Phase I: Patients receive oral hydroxychloroquine every other day for 2 weeks. Patients then receive oral hydroxychloroquine 1-3 times daily or every other day and bortezomib IV twice a week for 2 weeks. Treatment with hydroxychloroquine and bortezomib repeats every 3 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) for hydroxychloroquine is determined, additional patients are accrued to the phase II portion of the study. * Phase II: Patients receive hydroxychloroquine (at the MTD determined in phase I) and bortezomib as in phase I. Blood and bone marrow samples are collected periodically during the study for correlative studies by mass spectrometry, proteasome inhibition assays, pharmacokinetic analysis and assessment of aggresome formation, autophagy inhibition, and apoptosis by protein electrophoresis and serum free light-chain analysis. After completion of study treatment, patients are followed periodically.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Hydroxychloroquine Added to Bortezomib
Dose escalated by cohorts Hydroxychloroquine 200-600 mg pill every other day. Bortezomib 1.0-1.3mg/m2 IV, days 1, 4, 8, and 11 of each 21 day cycle.
Intervention: bortezomib
Hydroxychloroquine Added to Bortezomib
Dose escalated by cohorts Hydroxychloroquine 200-600 mg pill every other day. Bortezomib 1.0-1.3mg/m2 IV, days 1, 4, 8, and 11 of each 21 day cycle.
Intervention: hydroxychloroquine
Outcomes
Primary Outcomes
Overall response rate
Time Frame: Day 1 of each cycle (each cycle is 21 days)
This is assessed using International Working Group criteria.
Secondary Outcomes
- Effects of regimen on the autophagy pathway(at baseline, prior to bortezomib on Day1 and 8 of cycle 1, prior to bortezomib on Day 1 of cycle 2 (each cycle is 21 days))
- AV accumulation during therapy(Day 1 and 8 of the first cycle and on Day 1 of each subsequent treatment cycle (each cycle is 21 days))